Stearoyl-CoA desaturase 1 (SCD 1) is a critical microsomal enzyme that catalyzes the conversion of saturated fatty acid-CoAs to mono-unsaturated fatty acid-CoAs (at C-9 position) (DOBRZYN, A., et al., Obes. Rev., 2005, pp 169, Vol. 6; NTAMBI, J., et al., Curr. Opin. Lipidol., 2003, pp 255, Vol. 14). These mono-unsaturated fatty acid-CoAs, such as palmitoleic (C16) acid-CoA and oleic (C18) acid-CoA, are major building blocks in biosynthesis of lipids including phospholipids, triglycerides, cholesterol esters and wax esters (MIYAZAKI, M., et al., J. Lipid Res., 2002, pp 2146, Vol. 43). Four SCD isoforms (SCD 14) in rodents and two human genes (SCD 1 and 2) have been identified and characterized. SCD 1 (MIYAZAKI, M., et al., J. Biol. Chem., 2003, pp 33904, Vol 278; WANG, J., et al., Biochem. Biophys. Res. Commun., 2005, pp 735, Vol. 332), with ca. 85% identity across species (ZHANG, L., et a., Biochem. J., 1999, pp 255, Vol. 340), is abundantly expressed in liver and adipose tissue and is regulated by several nutritional and hormonal factors, such as insulin, cholesterol, and poly-unsaturated fatty acids (WATERS, K. M., et al., J. Biol. Chem., 1994, pp 27773, Vol. 269; NTAMBI, J. M., et al., J. Lipid Res., 1999, pp 1549, Vol. 40). Moreover, SCD 1 deficiency in mice, either naturally deficient Asebia mice (ZHENG, Y., et al., Nat. Genet., 1999, pp 268, Vol. 23) or laboratory-created SCD 1 knockout (SCD 1−/−) mice (NTAMBI, J. M. et al., Proc. Natl. Acad. Sci. U.S.A., 2002, pp 11482, Vol. 99), has been shown to reduce body adiposity, increase insulin sensitivity, and impart resistance to diet-induced obesity (NTAMBI, J. M., et al., Prog. Lipid Res., 2004, pp 91, Vol. 43). The SCD 1−/− mice also have lower levels of hepatic cholesterol esters and triglycerides (MIYAZAKI, M., et al., J. Biol. Chem., 2000, pp 30132, Vol. 275).
These observations indicated that inhibition of SCD 1 activity may serve as a potential treatment for obesity, type-II diabetes, and other related metabolic disorders.